Department of Genetics, Cell Biology and Development.
Stem Cell Institute, Minneapolis, Minnesota 55455, and.
Genetics. 2020 May;215(1):129-141. doi: 10.1534/genetics.120.303069. Epub 2020 Mar 10.
The vertebrate limb serves as an experimental paradigm to study mechanisms that regulate development of the stereotypical skeletal elements. In this study, we simultaneously inactivated using and in mouse embryos, and found that their combined function regulates development of the proximal-anterior skeletal elements in hindlimbs. The ; double knockout exhibits severe defects in the femur, tibia, and anterior digits, distinct defects compared to other allelic series of ; We found that regulates expression prior to hindlimb outgrowth. Further expression analysis indicated that genes and GLI3 are severely downregulated in the ; double knockout hindlimb bud. In contrast, PLZF expression is reduced but detectable in ; double knockout limb buds, and SALL4 is expressed in the ; double knockout limb buds. These results indicate that , , and genes downstream of , regulate femur and tibia development. In the autopod, we show that negatively regulates Hedgehog signaling, which allows for development of the most anterior digit. Collectively, our study illustrates genetic systems that regulate development of the proximal-anterior skeletal elements in hindlimbs.
脊椎动物肢体可作为研究调控典型骨骼元素发育机制的实验范例。在这项研究中，我们同时使用 和 在小鼠胚胎中进行了失活，发现它们的共同功能调节了后肢近前骨骼元素的发育。与其他等位基因系列的 相比， ; 双敲除表现出股骨、胫骨和前指的严重缺陷。我们发现 在肢体生长之前调节 的表达。进一步的表达分析表明，在 ; 双敲除后肢芽中， 和 GLI3 的表达严重下调。相比之下， 在 ; 双敲除肢芽中的表达减少但可检测到，而 在 ; 双敲除肢芽中表达。这些结果表明，位于 下游的 、 和 基因调节股骨和胫骨的发育。在后足，我们表明 负调控 Hedgehog 信号，从而允许最前一个指的发育。总的来说，我们的研究说明了调节后肢近前骨骼元素发育的遗传系统。
